Preclinical evaluation of anti-cadherin 3 human-mouse chimeric monoclonal antibody FF-21101 radioimmunotherapy

Objectives CDH3 (Cadherin 3), overexpressed in various cancers, is a potential therapeutic target. We previously reported (SNM 2010) tumor high uptake of ⁶⁷Ga labeled anti CDH3 mouse monoclonal antibody and significant growth inhibition of ⁹⁰Y labeled antibody in human lung carcinoma bearing mouse model. Motivated by these results, we developed a DOTA conjugated anti CDH3 human-mouse chimeric monoclonal antibody FF-21101. Here we report the biodistribution and therapeutic effects of ¹¹¹In and ⁹⁰Y labeled FF-21101 in animal experiments.

Methods Human lung adenocarcinoma NCI-H1373 and squamous cell carcinoma EBC-1 were used in mouse xenograft model. ¹¹¹In or ⁹⁰Y labeled FF-21101 was injected into the tail vein of tumor bearing mice. Biodistribution was estimated by gamma camera imaging and dissected organ count. Efficacy of ⁹⁰Y labeled antibody was evaluated by tumor size and body weight. ¹¹¹In labeled FF-21101 was also administrated to cynomolgus monkeys and evaluated by gamma camera imaging. WinNonlin and Olinda were used for analysis of PK parameters and absorbed dose, respectively.

Results High tumor accumulation of ¹¹¹In-labeled FF-21101 was observed in mouse xenograft model. Maximum tumor uptake was 48% ID/g (NCI-H1373) and 30% ID/g (EBC-1), respectively. Significant tumor growth inhibition was observed in both tumor models. Tumor growth was completely inhibited at day 60 in the 7.4 MBq/mouse group. Body weight initially decreased, but recovered within the first 3 weeks. In monkey experiments, relatively higher uptake in liver and spleen was observed. However, human dose extrapolation of ⁹⁰Y labeled FF-21101 from monkey planar image data suggested acceptable uptake by bone marrow and other critical organs.

Conclusions FF-21101 radioimmunotherapy exhibited high anti-tumor efficacy and low toxicity in animal experiments. Extrapolation from monkey data suggests potential human clinical application.